Tuberculosis (TB) is one of the most common infectious diseases known to man. Though effective treatments using four drugs: rifampincin, isoniazid, ethambutol and pyrazinamide are available, the high doses required and the lengthy duration of the treatment has resulted in poor compliance from TB patients. The failure of these anti-tubercular treatments is essentially due to partial compliance or non-compliance with recommended therapy. Moreover, it has been found that partial compliance with recommended therapy results in drug resistance. A patient who receives no therapy at all transmits non-resistant tubercle bacilli to others, whereas a patient who receives partial therapy develops multi-drug resistance and transmits drug-resistant tubercle bacilli. Drug resistance in TB patients predominantly arises as a result of multiple interruptions of treatment. When using single-drug formulations, patients are more prone to interrupt treatment with some drugs and not others, thereby creating a risk of monotherapy and selection of drug-resistant mutations.
To improve patient compliance and control drug resistance, the WHO recommends the use of a fixed-dose combination (FDC). These anti-tuberculosis drugs can be given as single-drug formulations or as fixed-dose combinations in which two or more anti-tuberculosis drugs are present in fixed proportions in the same formulation. In 1999 the WHO recommended a four-drug fixed-dose combination to improve compliance by reducing the number of tablets required to be consumed. Although four-drug FDCs are available, their effectiveness is hampered due to a reduction in the bioavailability of rifampicin in the presence of the other drugs released by the tablets. Various researchers have worked on several aspects of this problem with FDC tablets and several suggestions are recorded in the literature.
WO 02/087547 discloses a wet granulation process for manufacture of tablets containing rifampicin, isoniazid, pyrazinamide and ethambutol HCl by 3-step or 4-step granulation, without use of a surfactant. The 3-step or 4-step granulation shows better dissolution profile of rifampicin than a 2-step granulation process. This might be attributed to the longer disintegration time of the tablets granulated by a 2-step granulation process. Furthermore, the experiment was conducted to study the effect of a surfactant on the composition prepared from the process disclosed in WO 02/087547. The results show that use of a surfactant, such as sodium lauryl sulfate (SLS), affected the in vitro dissolution of rifampicin adversely and the composition without SLS shows better in vitro dissolution of rifampicin.
US 2005/0249804 discloses a composition of rifampicin, isoniazid, pyrazinamide and ethambutol in a stable complex. When the active ingredients are mixed together after treatment, they will not react with each other. The process for preparing said composition needs only wet granulation, drying, mixing and lubricating with surfactant and compression into tablet form. The composition avoids the need for coating the product.
US 2005/0084455 provides a biodegradable inhalable micro-particle composition useful for target-specific drug delivery to manage pulmonary TB. This composition is comprised of two anti-tubercular drugs and a biodegradable polymer in the ratio of 1:2 to 2:1 for drug delivery.
U.S. Pat. No. 7,195,769 discloses an oral pharmaceutical composition comprised of rifampicin and isoniazid, wherein rifampicin is formulated to release in the stomach and isoniazid is formulated for an extended or delayed enteric release so that the release of rifampicin and that of isoniazid take place at separate locations inside the gastrointestinal tract and the bioavailability of rifampicin is enhanced by preventing its degradation caused by the presence of isoniazid.
In view of degradation of rifampicin in an acidic environment, in particular in the presence of isoniazid, the invention of CN 1437946 provides a rifampicin release system wherein rifampicin is released in the intestine while the other drugs, such as isoniazid, pyrazinamide and ethambutol HCl are released in the stomach, or wherein isoniazid is released in the intestine while the other drugs are released in the stomach. CN 1408354 discloses a tablet-in-tablet pharmaceutical composition, wherein the core of the composition comprises rifampicin and the outer layer comprises isoniazid and pyrazinamide to avoid the formation of 3-formyl rifampicin SV isoniazid.
However, there is still a need in develop an anti-tubercular pharmaceutical composition with improved stability and bioavailability.